antioxidants Review Structure–Biological Activity Relationships of Extra-Virgin Olive Oil Phenolic Compounds: Health Properties and Bioavailability Paloma Rodríguez-López 1,2, Jesús Lozano-Sanchez 1,2,* , Isabel Borrás-Linares 2, Tatiana Emanuelli 3 , Javier A. Menéndez 4 and Antonio Segura-Carretero 2,5 1 Department of Food Science and Nutrition, University of Granada, Campus Universitario s/n, 18071 Granada, Spain; [email protected] 2 Research and Development Functional Food Centre (CIDAF), Health Science Technological Park, Avenida del Conocimiento 37, Edificio BioRegión, 18016 Granada, Spain; [email protected] (I.B.-L.); [email protected] (A.S.-C.) 3 Department of Food Technology and Science, Center of Rural Sciences, Federal University of Santa Maria, Camobi 97105-900, Santa Maria, RS, Brazil; [email protected] 4 Catalan Institute of Oncology ProCURE (Program Against Cancer Therapeutic Resistance), Ctra. França s/n, Hospital Dr. Josep Trueta de Girona, 17007 Girona, Catalonia, Spain; [email protected] 5 Department of Analytical Chemistry, Faculty of Sciences, University of Granada, 18071 Granada, Spain * Correspondence: [email protected] Received: 7 July 2020; Accepted: 28 July 2020; Published: 1 August 2020 Abstract: Extra-virgin olive oil is regarded as functional food since epidemiological studies and multidisciplinary research have reported convincing evidence that its intake affects beneficially one or more target functions in the body, improves health, and reduces the risk of disease. Its health properties have been related to the major and minor fractions of extra-virgin olive oil. Among olive oil chemical composition, the phenolic fraction has received considerable attention due to its bioactivity in different chronic diseases. The bioactivity of the phenolic compounds could be related to different properties such as antioxidant and anti-inflammatory, although the molecular mechanism of these compounds in relation to many diseases could have different cellular targets. The aim of this review is focused on the extra-virgin olive oil phenolic fraction with particular emphasis on (a) biosynthesis, chemical structure, and influence factors on the final extra-virgin olive oil phenolic composition; (b) structure–antioxidant activity relationships and other molecular mechanisms in relation to many diseases; (c) bioavailability and controlled delivery strategies; (d) alternative sources of olive biophenols. To achieve this goal, a comprehensive review was developed, with particular emphasis on in vitro and in vivo assays as well as clinical trials. This report provides an overview of extra-virgin olive oil phenolic compounds as a tool for functional food, nutraceutical, and pharmaceutical applications. Keywords: extra virgin olive oil phenolic compounds; chemical structure; bioactivity; bioavailability 1. Introduction Extra-virgin olive oil (EVOO) represents one of the symbols of the highly valued Mediterranean diet. It is the typical lipidic source in the cuisine of the Mediterranean countries and its consumption has been associated with reduced morbidity and slowing disease progression such as cardiovascular, neurodegenerative, or even cancer diseases [1–11]. On the basis of all of these considerations, EVOO could be considered as a functional food. Although the European regulation does not have a current definition for functional food, it could be defined as follows: “food products can only be considered Antioxidants 2020, 9, 685; doi:10.3390/antiox9080685 www.mdpi.com/journal/antioxidants Antioxidants 2020, 9, 685 2 of 17 functional if together with the basic nutritional impact it has beneficial effects on one or more functions of the human organism, thus either improving the general and physical conditions or/and decreasing the risk of diseases evolution” [12,13]. The beneficial impact of EVOO in the human organism is well established, and it is due to its composition. The predominant fatty acid present in the virgin olive oil is monounsaturated oleic acid (68–82% of the total fatty acids in olive oil), which has been widely studied, and its benefits have been established [7,8,10,11]. Moreover, there is a fraction of microconstituents, such as phytosterols, squalene, tocopherols, phenolic compounds, terpenic acid derivatives, etc. Among them, phenolic compounds, which are known for their remarkable antioxidant activity [1,2,14,15], have attracted the attention of researchers belonging to different knowledge areas. They are characterized by a complex mixture of compounds, which occur in the form of simple phenols, lignan derivatives, secoiridoids, and flavonoids. Secoiridoids and alcoholic phenols (mainly hydroxytyrosol) are present in high amounts in virgin and extra-virgin olive oil [2,5]. These phenolic compounds are characterized by a broad spectrum of biological activities, such as reducing the morbidity and slowing the progression of diseases associated with oxidative stress, due to their well established antioxidant activity [16]. Indeed, over the last decades, research into EVOO phenolic compounds has shown the role that these compounds may play in the prevention or slowing down the development of certain pathologies [17–19]. For this reason, The European Food Safety Authority (EFSA) has approved in 2011 a health claim stating that the dietary intake of virgin olive oil (poly) phenols is able to protect blood lipids from oxidative damage. The panel considers that in order to bear the claim, 5 mg of hydroxytyrosol and its derivatives should be consumed daily [20,21]. In addition to their widely studied beneficial effects, the latest research has been focused on the metabolic pathways followed by these compounds, their effects on target organs, and even possible delivery strategies as a means of increasing their bioavailability. The present review studied the relevance of EVOO phenolic compounds with particular emphasis on (a) chemical structure, biosynthesis, and influence factors on the final EVOO phenolic composition; (b) structure–antioxidant activity relationships and other molecular mechanisms in relation to the prevention of many diseases; (c) bioavailability and controlled delivery strategies; (d) alternative source of olive bio-phenols. Thus, the objective of this work is summarizing the scientific state of the art as well as revealing the most innovative arguments for future research based on potential clinical relevance of EVOO phenolic compounds. 2. Methods A literature search was conducted on four electronic databases (PubMed, CrossRef, Scopus and Web of Science). Furthermore, DeCS was used as a descriptor of terms and Mendeley was the reference manager. 2.1. Search Strategy Search terms related to studies of EVOO polyphenols were combined in the following strategies: a) EVOO/Extra virgin olive oil/Olive Oil AND phenol/phenols/polyphenols/phenolic compounds AND properties/health/benefits/oxidative stress/oxidative damage/antioxidant/(anti)cancer/ (anti)inflammatory/cardiovascular/digestive disorders/metabolic syndrome; b) EVOO/Extra virgin olive oil/Olive Oil AND phenol/phenols/polyphenols/phenolic compounds AND chemical structure/ biosynthesis/bioavailability/absorption/distribution/metabolism/delivery strategies/nanoformulations /sources/synthesis/dopamine. Keyword searches allowed identifying the relevant literature adequately narrowed down to our research focus using the inclusion criteria described below without limiting the research to specific objectives of this work (e.g., EVOO phenolic compounds and health benefits, biosynthesis and bioavailability). Antioxidants 2020, 9, 685 3 of 17 2.2. Inclusion Criteria Literature review and research articles published since 1 January 2010, with no restriction of language. Due to the high heterogeneity of the proposed objectives, no quality-assessment scale systems were used to evaluate the compiled studies. Manuscript screening was carried out checking the title and abstract or reading the full text. Regarding the possible beneficial heath properties of phenolic compounds, only those trials carried out with phenolic compounds from extra-virgin olive oil and those that were chemically characterized were included. Experimental trials performed in vitro and in vivo (animals and humans) were included and classified according to their potential studied property. Acute and long-term trials were selected to be analyzed in order to compile the described effects over the time-to-event endpoints. 3. Results and Discussion The literature search provided 2976 studies, which were identified before duplicates were discarded. Among these, a total of 116 articles were finally included after applying the inclusion criteria described in Section2: (a) 29 articles including information about biosynthesis, chemical structure, and influence factors on the final EVOO phenolic composition; (b) 42 articles related to structure–antioxidant activity relationships and other molecular mechanisms in relation to many diseases; (c) 22 of bioavailability and controlled delivery strategies; (d) 15 of alternative source of olive biophenols. Results reveal the most innovative arguments for future research. The most-studied EVOO phenolic compounds were phenolic alcohols and secoiridoids. 3.1. Chemical Structure, Biosynthesis, and Influence Factors on EVOO Phenolic Composition EVOO phenolic compounds have been classified according to their chemical structure into the following main classes: phenolic acids, lignans, flavonoids, phenolic alcohols, secoiridoids, and hydroxy-isocromans [2,5,14,22]. Table1